It is known to the art to dispense various types of biologically active agents such as drugs, hormones, nutrients, pesticides, fertilizers, bacteriocides and fungicides, for example, from a source into an environment of use. In their broadest context, these devices comprise a source or reservoir of the active agent to be dispensed which is maintained in mass transfer relationship to the environment of use. In those situations in which the rate at which the active agent is released is not particularly critical, it is possible to achieve adequate results merely by placing a mass of the material in the environment and allowing it to dissolve or diffuse or otherwise disperse into the environment. In other circumstances, however, such as where pharamaceutical products, pesticides or nutrients, for example, are involved or where it is necessary to extend delivery over a long period of time in a predictable fashion; it becomes necessary to more precisely control the release rate of the active agent from its source. When extremely precise control release of the active agent from the device is required, various structures, such as those shown in U.S. Pat. Nos. 3,854,480, 3,921,636, 3,926,188, 3,948,262, 3,993,072, 4,201,211, 4,031,894, 4,057,619, 4,286,592 and 4,292,965, all of which are incorporated herein by reference are known to the art. These devices utilize, in one form or another, release rate controlling barriers or membranes interposed between the source of the drug and the environment of use to control release rates. While such devices can be designed to produce extremely precise release rates, their structure is relatively complex, which complexity adds to the cost of the device.
At the other extreme where precise control is not required, it has been known to disperse the biologically active agent in a cream, ointment, gel or polymeric matrix which is then placed on or in the environment of use and the active agent released therefrom by diffusion. Typical systems include various medicated creams and gels used to dispense nitroglycerin, antihistamines and steroids for example, which are commercially available and such devices as shown by U.S. Pat. Nos. 4,024,871, 3,342,183, and 3,598,127.
The rate of release of a dispersed active agent at a concentration greater than saturation from such matrices has been extensively studied and analyzed. (See T. Higuchi, Rate of Release of Medicaments from Ointment Base Containing Drugs in Suspension, J. Pharm. Sci. Vol. 50, No. 10, P. 874-875 (October 1961); T. Higuchi, Mechanisms of Sustained Action Medication, J. Pharm. Sci., Vol. 52, No. 12, P. 1145-1149 (December 1963)). These papers show that the rate of active agent release from such systems normally will vary inversely with the square root of the time (t.sup.-1/2) that the system is in operation. Such systems, accordingly, are characterized by an initial high release rate which then decreases relatively rapidly and continuously over the lifetime of the device. While these devices are relatively inexpensive to produce, merely requiring formation of an active agent loaded matrix, their application is limited to those situations in which this variation in release rate with time can be tolerated or in which some other element controls the rate of absorption by the body (such as the stratum corneum of the skin, for example).
Since simply dispersing an active agent through a matrix has significant cost advantages, various approaches have been proposed to improve the release characteristics of matrix systems without resorting to the use of rate controlling membranes. Geometrical approaches have been suggested, Controlled Release of Bioactive Materials, Edited by Richard Baker, p. 177-187, Academic Press, New York (1980) as have systems based on the relationship between solubility and diffusion coefficient, Chien et al., Controlled Drug Release From Polymeric Delivery Devices II: Differentiation Between Partition Controlled and Matrix Controlled Drug Release Mechanisms, J. Pharm. Sci., Vol. 63, No. 4, p. 515-519 (April 1974).
With respect to matrix systems comprising a matrix containing a suspension of a solute; the mass (M) transferred across a boundary per unit area and per unit of time (t) will be a direct function of the concentration of the solute in the matrix at saturation (C.sub.s) and the diffusion coefficient (D.sub.s) of the solute in the matrix and an inverse function of the distance across the boundary (h) according to Fick's law: EQU (dM/dt)=D.sub.s C.sub.s /h
As shown by Higuchi above, when an active agent is suspended in a stationary matrix at an initially uniform concentration, the agent is first released from the exposed surface causing a depletion of the suspended solute in the matrix immediately adjacent to the releasing surface. Once the concentration of the solute in this zone has been reduced to the saturation concentration, a depletion zone is formed across which a concentration gradient exists. For the ideal system with an infinite sink, the gradient ranges from zero at the releasing surface to C.sub.s at the interior boundary of the depletion zone. As agent release from the surface continues, the thickness of the depletion zone will increase. It is the distance between the surface of the matrix through which the agent is released and the interior boundary of the depletion zone which is the value of "h" in the above equation. As h increases, the time required for the agent to flow from the boundary of the depletion zone to the releasing surface increases, thereby decreasing the amount of active agent being transferred to the surface per unit of time.
In view of the above, it has also been proposed to compensate for the increase in the thickness of the depletion zone by increasing the concentration of the solute in the matrix, as the distance from the releasing surface increases. Various approaches have been suggested to accomplish this such as shown in U.S. Pat. No. 3,923,939 in which the solute is leached from a portion of the matrix adjacent to the surface; South African patent publication No. 728,198, June 15, 1977, which discloses a dispensing device comprising a core and an outer layer in which the concentration of the dispersed active agent in the core and outer layer are different (either higher or lower) and South African patent application 80/3009 filed May 20, 1980, which discloses a transdermal drug administration device comprising a polyacrylate film in which the concentration of the drug to be dispersed increases with increasing distance from the releasing surface.
While these approaches can improve the release characteristics of the device, the manufacturing techniques required to obtain the desired concentration gradient, either by forming separate compositions having different concentrations of solute dispersed in the matrix and thereafter sequentially forming the end item as in the South African patent, or by sequentially depositing additional amounts of the active agent onto a substrate as in the South African patent application or by extracting the surface of the finished device as in the U.S. and the South African patents; may closely approach the cost associated with manufacturing a rate controlling membrane system having superior properties.
According to our invention, however, we have devised a dispensing device and methods for fabricating and using the same in which a matrix composition containing a dispersion of the active agent solute at a concentration above saturation, is combined with a matrix composition containing the solute at a concentration no greater than saturation to produce an active agent dispensing device having a release rate, over a substantial portion of its life which does not vary as a function of t.sup.-1/2. We are able to accomplish this desired result by designing our system such that the actual concentration of the dispersed solute in the undepleted zone of the device remains constant with time while the effective concentration of the solute increases with time, or in the alternative, varies in other predetermined patterns.
It is accordingly an object of this invention to provide a dispersion-type active agent dispenser having improved release characteristics.
It is another object of this invention to provide a monolithic active agent dispenser comprising an active agent solute suspended within a matrix at a substantially constant concentration greater than saturation and means for varying the effective concentration of said solute in a predetermined manner with time.
It is another object of this invention to provide a dispersion type active agent dispenser suitable for use in a transdermal delivery system.
It is another object of this invention to provide methods for manufacturing dispersion type active agent dispensers.
These and other objects of this invention will be readily apparent from the following description with reference to the accompanying drawings wherein: